Mosquito-borne diseases are an excellent example of emerging and resurging diseases of global importance causing significant public health threats around the world. Disease caused by chikungunya virus (CHIKV) is an excellent example of globalization of a vector-borne disease, and is transmitted primarily by Aedes aegypti and Aedes albopictus. The potential for establishment of a CHIKV transmission cycle in new ecological niches with competent vectors and susceptible human population is a credible threat and must be treated seriously. Chikungunya virus is transmitted though the bite of an infected mosquito during blood feeding. Mosquito saliva creates a privileged immunosuppressed cutaneous microenvironment, that facilitates establishment of infection and virus dissemination. We have recently shown that CHIKV-infected Ae. aegypti saliva induces TH2 type response at the bite site, and suppressed antiviral factors IFN- and TLR-3. However, the implications of this immunologically privileged environment with impaired antiviral effector functions in the establishment of CHIKV infection and disease progression is not yet elucidated. This will be the first study to our knowledge to investigate the role of Ae. aegypti saliva in CHIKV transmission and dissemination. Based on previous reports, it is clear that the effects of mosquito saliva on a pathogen can be highly variable, sometimes enhancing infection and sometimes having a protective effect. As a consequence, before extrapolating from the results of one vector-pathogen relationship to another, it is critical that we study more associations so that we can identify the underlying mechanisms of the vector-virus-vertebrate relationship. The proposed work on an increasingly important pathogen, using innovative approaches and methodologies, represents a significant contribution to our knowledge base on this subject. PUBLIC HEALTH RELEVANCE: The potential for establishment of a CHIKV transmission cycle in new ecological niches with competent vectors and susceptible human population is a credible threat and must be treated seriously. Proposed studies will advance understanding of the effects of mosquito saliva in CHIKV transmission and dissemination.